On the big screen, he was a sailor in Hitchcock's "Marnie" and Bette Davis' victim in "Hush ... Hush, Sweet Charlotte" (both 1964). In 1966, Dern hooked up with Roger Corman and appeared in a number of films for American International, including "The Wild Angels" (1966), "The St Valentine's Day Massacre" and "The Trip" (both 1967) and "Bloody Mama" (1970). The actor also began to display his versatility beginning with the taut drama "They Shoot Horses, Don't They?" and the Western spoof "Support Your Local Sheriff" (both 1969). He won critical praise as the zealous basketball coach in Jack Nicholson's "Drive, He Said" (1971), the rebellious botanist in Douglas Trumbull's "Silent Running" (1972), the con man known as "The King of Marvin Gardens" (also 1972) and as the wealthy, spoiled Tom Buchanan in Jack Clayton's "The Great Gatsby" (1974). Dern had one of his best screen roles as the disillusioned Vietnam veteran who returns to find his wife involved with a paraplegic in Hal Ashby's "Coming Home" (1978). Other highlights include "That Championship Season" (1982), in which he was mayor desperately attempting to win re-election and "After Dark, My Sweet" (1990), as a weasely con man.

Since the early 1990s, Dern has also turned up frequently in TV-movies of varying qualities, and continued to make usually small appearances on the big screen in films including "Diggstown" (1992), "Mulholland Falls" (1996), "Down Periscope" (1996), "Last Man Standing" (1996), "The Haunting" (1999), "All the Pretty Horses" (2000) and "The Glass House" (2001). Dern got one of his highest profile late-career roles when he appeared in writer-director Patty Jenkins' "Monster" (2003), the story of real-life female serial killer Aileen Wournos, playing Thomas, one of the only trusted men in Wournos' tragic life.